Multiple Sclerosis (MS) is an autoimmune disease which occurs when T lymphocytes invade the CNS and damage the oligodendrocytes responsible for the maintenance of axonal myelin sheaths, resulting in impaired neuronal activity. The disease is characterised symptomatically by varying degrees of visual, motor, sensory and cognitive dysfunction. MS is broadly classified into four categories, defined by the progress pattern of the disease (Lublin and Reingold, 1996). For most patients, the disease begins as relapsing-remitting MS, characterised by periods of spontaneous remission between symptomatic relapses. This often progresses to a form where remissions cease, resulting in continuous neurological decline, a type classified as secondary progressive MS. In cases where no remission occurs after the onset of the disease and subsequent worsening of neurological symptoms the disease is classified as primary progressive MS. The final category, progressive-relapsing MS, is the rarest subtype, and is characterised by a steady increase in severity of the neurological impairments, with superimposed acute attacks of greater severity.
Although there is some evidence for genetic factors increasing the risk of MS (Sadovnick, 1996), the “trigger” which causes the disease is unknown and occurrence cannot be predicted, eliminating the possibility of preventative strategies being developed in the foreseeable future. The prevalence rate of MS has been estimated at approximately 1 in 700, affecting females at approximately twice the rate of males, although prevalence estimates vary greatly depending on region (Rosait, 2001). As a progressive disease with considerable resultant disability, the condition is associated with a high cost of illness, a significant proportion of which relates to drug costs. In the US in 2004, 98.1% of all MS patients used medicines at a mean cost of $18,628 per patient per year, of which $16,050 was the cost of disease modifying drugs (Kobelt et al, 2005). In Europe, cost of drug treatment is highest at the earliest stage of disease, and varies between countries, from 4,324 per patient per year in the UK to 12,881 in Germany (Kobelt et al, 2006). Despite this significant expenditure on treatment, current pharmaceutical therapies, all of which target the immune system's role in the disease, are limited to slowing the progress of the disease or decreasing the rate of disease recurrence, and are largely ineffective in the treatment of progressive disease forms.
2-oxopyrrolidine compounds are known to effect cerebral function (Japanese Patent Application Publication No: 56.2960/1981). In particular, it has been suggested in the literature that NEFIRACETAM (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide) may improve cerebral function and cognition (Moriguchi et al. 2009, Moriguchi et al. 2008), improve intellectual ability following stroke (US Patent Application No:2002/0055534), and have anticonvulsant and neuroprotective effects in animal models (Kitano et al. 2005).
It is an object of the invention to overcome at least one of the above problems.
Statements of Invention
The invention is based on the surprising finding that 2-oxopyrrolidine compounds (hereafter “Active”) are capable of maintaining the integrity (for example, preventing demyelination and/or promoting remyelination) of axonal myelin sheaths in cell and animal models of diseases associated with CNS or PNS demyelination. Data is provided below which clearly shows that the Active accelerates myelin repair in axonal cells that have been damaged in a cuprizone animal model of demyelination, and restores myelin expression following 6 days of treatment (See FIGS. 4A to 4C). Data is also provided which shows the effects of the Active is a non-immune mediated effect (See FIGS. 2 and 3) and that the effects are achieved using four different species of the 2-oxopyrrolidine class of compounds (See FIG. 1). Thus, the invention broadly relates to the use of the Active in the causal treatment of a disease caused by axonal demyelination, in which the Active maintains the integrity of myelination (for example by promoting remyelination, and/or preventing demyelination, of the axonal sheaths). The invention is particularly directed to the causal treatment of CNS demyelination diseases, for example MS, especially primary progressive MS and/or relapse remitting MS, and PNS demyelination diseases, for example Charcot-Marie-Tooth Disease. The Active of the invention may be suitably administered when a patient is in relapse (i.e. upon relapse), and be continued while the patient is in relapse, with a view to attenuating the severity of the relapse, and/or accelerating disease remission. Alternatively, the Active may be administered continuously with a view to prolonging the remission period, and/or attenuating the severity of the relapse, and/or preventing relapse. The invention also relates to the use of the Active as a treatment for symptoms of demyelination disease, especially MS, selected from vision deficits, motor control deficits, and sensation deficits.
Accordingly, the invention broadly relates to an Active for use in the causal treatment or prevention of a disease or condition associated with central nervous system (CNS) or peripheral nervous system (PNS) demyelination in a mammal by maintaining the integrity of myelination of axonal cells.
In this specification, the term “maintaining the integrity of myelination of axonal cells” should be understood to mean effecting remyelination of axonal cells, inhibiting or preventing demyelination of axonal cells, or both. The term “causal” treatment should be understood to mean a treatment of demyelination as an underlying cause of the disease, and to exclude treatments that are intended to directly address clinical symptoms of the disease (symptomatic treatment).
In another aspect, the invention broadly relates to a method for the treatment or prevention of a disease or condition associated with central nervous system (CNS) or peripheral nervous system (PNS) demyelination in a mammal by maintaining the integrity of myelination of axonal cells, the method comprising a step of administering a clinically effective amount of an Active to an individual in need thereof.
In another aspect, the invention relates to a method for treating a relapse, especially an acute relapse, of a disease or condition associated with central nervous system (CNS) or peripheral nervous system (PNS) demyelination in a mammal by maintaining the integrity of myelination of axonal cells., the method comprising the step of administering a clinically effective amount of an Active to the mammal upon relapse of the disease or condition. Preferably, the administration of the clinically effective amount of the Active is continued during a period of relapse of the disease or condition and is preferably discontinued upon remission of the disease or condition.
In another aspect, the invention relates to a method of prolonging a period of remission of a disease or condition associated with central nervous system (CNS) or peripheral nervous system (PNS) demyelination in a mammal by maintaining the integrity of myelination of axonal cells, the method comprising the step of administering a clinically effective amount of an Active to the mammal during a period of remission of the disease or condition. Preferably, the administration of the clinically effective amount of the Active is continued during a period of relapse of the disease or condition.
In another aspect, the invention relates to a non-immune mediated therapy (preferably a non-immune mediated causal therapy) for a disease or condition associated with central nervous system (CNS) or peripheral nervous system (PNS) demyelination in a mammal, especially multiple sclerosis (MS), especially primary progressive MS, the method comprising a step of administering a clinically effective amount of an Active to the mammal in an amount sufficient to result in a clinically significant remyelination, or inhibition of demyelination, of axonal sheaths in the mammal. The term “non-immune mediated therapy” should be understood to mean a therapy which is not directed at dampening down of the immune response in the mammal.
In one embodiment, the methods and uses of the invention comprise a combination therapy or use comprising the administration of an Active in parallel with administration of an immune mediated therapeutic. The term “immune mediated therapeutic” or “immunosuppressant” are used interchangeably and should be understood to mean a causal therapeutic that is aimed at modulating the immune response in a mammal to prevent, inhibit or ameliorate demyelination of axonal sheaths of CNS or PNS neuronal cells. Examples of immune mediated therapeutics or immunosuppressants are well known in the field, and include Natalizumab or TYSABRI (Elan), Interferon beta 1b (BETASERON), Interferon beta 1a (AVONEX), glatiramer acetate or COPAXONE (Teva), and daclizumab (ZENEMAX). The Active may be administered at the same time as the immune mediated therapeutic, or the two medicaments may be administered in a staggered manner. In one embodiment, the Active and immune mediated therapeutic are provided in a single unit dose form, for example, a liquid or tablet or the like.
Thus, in a further embodiment, the invention relates to a combination therapy for a disease or condition associated with central nervous system (CNS) or peripheral nervous system (PNS) demyelination in a mammal, for example multiple sclerosis, the method comprising a step of treating the mammal with (a) an immune mediated therapeutic to dampen or suppress an immune mediated response in the mammal in tandem with (b) an Active to promote remyelination of CNS or PNS neurons.
In one aspect, the invention relates to a method for the causal treatment of diseases or conditions associated with CNS or PNS demyelination in a human subject by inhibiting, ameliorating or reversing demyelination of CNS or PNS neuronal cells, the method comprising the steps of administering to the subject an amount of the Active effective to cause a clinically significant level of inhibition, amelioration, or reversal of demyelination of a CNS or PNS neuronal cells.
In another aspect, the invention relates to a method for inhibiting, ameliorating or reversing demyelination of CNS or PNS cells in a human subject in need thereof, the method comprising the steps of administering to the subject an amount of the Active effective to inhibit, ameliorate, or reverse demyelination of a CNS or PNS neuronal cells.
In another aspect, the invention relates to a method for preventing, or slowing the progression of diseases or conditions associated with CNS or PNS demyelination in a human subject by inhibiting, ameliorating or reversing demyelination of CNS or PNS cells, the method comprising the steps of administering to the subject an amount of the Active effective to inhibit, ameliorate, or reverse demyelination of a CNS or PNS neuronal cells.
In another aspect, the invention relates to a method for the treatment of one or more symptoms of a disease or condition associated with CNS or PNS demyelination in a human subject, the method comprising the steps of administering to the subject an amount of the Active effective to inhibit, ameliorate, or reverse demyelination of a CNS or PNS cell type. The symptoms are typically selected from the group consisting of vision deficits, motor control deficits, sensation deficits, and cognitive function deficits. In a preferred embodiment, the symptoms are selected from vision, motor control, and sensation, deficits.
In a preferred embodiment of the invention, the Active is NEFIRACETAM.
In a preferred embodiment of the invention, the condition associated with CNS or PNS demyelination is MS.
Thus, in a particularly preferred embodiment, the invention relates to a method for treating one or more symptoms of MS in a mammal selected from vision deficits, sensation deficits, and motor control deficits by promoting remyelination and/or inhibiting demyelination of axonal myelin sheaths, the method comprising the step of administering to the subject a clinically effective amount of an Active.
In a further particularly preferred embodiment, the invention relates to a method for treating primary progressive MS in a human subject, especially symptomatic treatment of vision deficits, sensation deficits, and/or motor control deficits, and optionally cognitive function deficits, the method comprising the step of administering to the subject an amount of NEFIRACETAM effective to inhibit, ameliorate or reverse demyelination of axonal cells in the CNS.
In a further particularly preferred embodiment, the invention relates to a method for treating one or more symptoms of primary progressive MS in a human subject selected from vision deficits, sensation deficits, and motor control deficits, and optionally cognitive function deficits, the method comprising the step of administering to the subject an amount of NEFIRACETAM effective to inhibit, ameliorate or reverse demyelination of axonal cells in the CNS.
The invention also relates to a pharmaceutical formulation comprising a combination therapy of an immune mediated therapeutic of the type capable of reducing the length and/or degree of inflammation-mediated damage to insulating cells around nerve fibres, and an Active. Such a formulation would be especially suitable for causal or symptomatic treatment, or prevention of autoimmune demyelinating diseases or conditions.
In this specification, the term clinically effective amount” should be taken to mean an amount of Active which results in a clinically significant inhibition, amelioration or reversal of demyelination, or clinically significant remyelination, of CNS or PNS neuronal cells. Details of dosages of NEFIRACETAM that are readily tolerated and readily orally administered are described in the literature (Robinson et al. 2009). Suitably, the Active is administered at a dose of between 1 microgram and 50 milligrams daily, preferably between 1 milligram and 40 milligrams daily, more preferably between 5 milligrams and 40 milligrams daily.
2-oxopyrrolidine compounds (the “Active”) are described in Japanese Patent Application Publication No: 56.2960/1981 and in International Patent Application Publication No: WO2006113937, the contents of which are incorporated herein by reference. Thus, in this specification, the term “2-oxopyrrolidine compound” or “Active” refers to a compound of general formula I:
wherein R is hydrogen, hydroxyl or aminomethyl;    R′ is hydrogen or piperidinocarbonyl group;    R″ is hydrogen, aminocarbonylalkyl optionally N-substituted with a di(C1-C4)alkylamino-(C2-C4)alkyl group, anilinocarbonylalky optionally mono or disubstituted on the benzene ring with methyl, methoxy, or halogen; benzyl, optionally mono or disubstituted on the benzene ring with methyl, methoxy, or halogen;    wherein one or two of R, R′ and R″ is hydrogen;    with the provisos that when R′ is other than hydrogen, then R and R″ are both hydrogen, and    when R is other then hydrogen, then R′ is hydrogen, or a pharmaceutically acceptable salt thereof.
Examples of 2-oxopyrrolidine compound of general Formula (I) useful for the present invention are:    Piracetam: wherein R═R′═H, R″═CH2 CONH2 (aminocarbonylmethyl);    Aniracetam: wherein R═R′═H, R″═CH2 C6H4-pOCH3 (4-methoxybenzyl);    Oxiracetam: wherein R═OH, R′═H; R″═CH2 CONH2;    Pramiracetam: wherein R═R′═H, R″═CH2 CONHCH2 CH2 N[CH(CH3)2]2, (2-disiopropylaminoethyl)aminocarbonylmethyl;    Nefiracetam: wherein R═R′═H, R″═CH2 CONH-(2,6CH3)C6H3 (anilinocarbonylmethyl);    Nebracetam: wherein R═CH2 NH2 (aminomethyl), R′═H; R″═CH2 C6H5 (benzyl);    Fasoracetam: wherein R═R″═H, R′=piperidinocarbonyl;    Fasoracetam: wherein R═R″═H, R′=piperidinocarbonyl (see below);
Levetiracetam, wherein R═R′═H; R″=1-aminocarbonylpropyl (see below).

Other racetams included within the scope of the invention include Phenylpiracetam (Carphedon), Etiracetam, Nicoracetam (racetam structure bonded to niacin), Rolziracetam, Nebracetam, Imuracetam, Coluracetam (potential use in prevention and treatment of ischemic retinopathy and retinal and optic nerve injury), Dimiracetam, Brivaracetam, and Seletracetam.
In a preferred embodiment, the Active is selected from the group consisting of: PIRACETAM, ANIRACETAM, PRAMIRACETAM, NEBRACETAM, FASORACETAM, LEVETIRACETAM and OXIRACETAM. Ideally, the Active is selected from the group consisting of PIRACETAM, ANIRACETAM, LEVETIRACETAM and NEFIRACETAM. Ideally, the Active is NEFIRACETAM (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide).
The term “diseases or conditions associated with CNS or PNS demyelination” should be understood to mean a pathology in which axonal demyelination of a CNS or PNS neuronal cell types is an underlying cause of the symptoms of the pathology. Examples of these diseases/conditions include demyelinating diseases of the central nervous system such as:
Multiple sclerosis including relapse remitting MS (RRMS), primary progressive MS, secondary progressive MS, and progressive relapsing MS; Idiopathic inflammatory demyelinating diseases; Transverse myelitis; Devic's disease; Progressive multifocal leukoencephalopathy; Optic neuritis; and Leukodystrophies, and demyelinating diseases of the peripheral nervous system such as: Guillain-Barré syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy; anti-MAG peripheral neuropathy; Charcot-Marie-Tooth Disease; and Vitamin B12 deficiency (change->B12 deficiency causes subacute combined degeneration of the spinal cord . . . spinal cord is part of the CNS, disease is “combined” b/c of demyelination of the Dorsal Columns—decreased vibration and proprioception sensation—and Corticospinal Tract—upper motor neuron disease symptoms).
In one embodiment, the disease or condition is one associated with CNS demyelination. In another embodiment, the disease or conditions is associated with PNS demyelination.
In this specification, the term administering should be taken to include any form of delivery that is capable of delivering the Active to the CNS or PNS, including intravenous delivery, oral delivery, intramuscular delivery, intrathecal delivery, and inhaled delivery. Methods for achieving these means of delivery will be well known to those skilled in the art of drug delivery, and include:                Delivered intrathecally by mini-osmotic pump. (ref: Ignacio et al., Ann. N.Y. Acad. Sci. 2005, 1053: 121-136).        Intramuscular delivery directly into muscle(s) by syringe or mini osmotic pump (Azzouz et al., Nat. Med. 2005; 11(4):429-33).        Intraperitoneal—for systemic administration—directly administered to peritoneum by syringe or mini osmotic pump (Kieran et al., Nat Med 2004; 10(4):402).        Subcutaneous—for systemic administration—directly administered below the skin by syringe (Reinholz et al., Exp Neurol. 1999; 159(1):204-16).        Intraventricular—direct administration to the ventricles in the brain, by injection or using small catheter attached to an osmotic pump. (Sathasivam et al., 2005 Neuropath App Neurobiol; 31(5): 467)        Implant—can be prepared in an implant (eg small silicon implant) that will release Active.        Implant can be placed at muscles or directly onto the spinal cord (Kieran and Greensmith, 2004 Neurosci 125(2):427-39).        
Additionally, administration of an Active to humans and animals is described in the following publications:                Feys P, D′ hooghe M B, Nagels G, Helsen W F. The effect of levetiracetam on tremor severity and functionality in patients with multiple sclerosis. Mult Scler. 2009 March; 15(3):371-8. Epub 2009 Jan. 23. PubMed PMID: 19168602.        Groom A J, Smith T, Turski L. Multiple sclerosis and glutamate. Ann N Y Acad. Sci. 2003 May; 993:229-75; discussion 287-8.        Gusev E I, Bo{hacek over (i)}ko A N, Kol'iak E V, Karalkin A V, Kamchatov P R, Martynov M Iu. [The impact of microcirculation dysfunction on the clinical presentations of multiple sclerosis in patients above 45 years and the possible ways of correction of the vascular pathology]. Zh Nevrol Psikhiatr Im S S Korsakova. 2008; 108(5):25-31. Russian. PubMed PMID: 18577954.        Hawker K, Frohman E, Racke M. Levetiracetam for phasic spasticity in multiple sclerosis. Arch Neurol. 2003 December; 60(12):1772-4. PubMed PMID: 14676055.        Le D T, Shin C, Jackson-Friedman C, Lyden P D. (2001) Quantitative effects of nefiracetam on spatial learning of rats after cerebral embolism. J Stroke Cerebrovasc Dis. 10:99-105.        Mula M, Sander J W. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf. 2007; 30(7):555-67. Review. PubMed PMID: 17604407.        Murphy K J, Foley A G, O'connell A W, Regan C M. (2006) Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing. Neuropsychopharmacology. 31:90-100        Papacostas S S, Papathanasiou E S, Myrianthopoulou P, Stylianidou G. Tuberous sclerosis successfully treated with levetiracetam monotherapy: 18 months of follow-up. Pharm World Sci. 2007 August; 29(4):350-2. Epub 2007 Mar. 1. PubMed PMID: 17333500.        Rossi S, Mataluni G, Codecà C, Fiore S, Buttari F, Musella A, Castelli M, Bernardi G, Centonze D. Effects of levetiracetam on chronic pain in multiple sclerosis: results of a pilot, randomized, placebo-controlled study. Eur J Neurol. 2009 March; 16(3):360-6. PubMed PMID: 19364364.        Solaro C, Brichetto G, Capello E, Abuarqub S, Sanguineti V. Activity, tolerability and efficacy of levetiracetam on cerebellar symptoms in multiple sclerosis patients: a pilot kinematic study. Eur J Neurol. 2008 June; 15(6):619-26. PubMed PMID: 18474077.        Striano P, Coppola A, Vacca G, Zara F, Brescia Morra V, Orefice G, Striano S. Levetiracetam for cerebellar tremor in multiple sclerosis: an open-label pilot tolerability and efficacy study. J Neurol. 2006 June; 253(6):762-6. Epub 2006 May 12. PubMed PMID: 16683063.        Takeo S, Niimura M, Miyake-Takagi K, Nagakura A, Fukatsu T, Ando T, Takagi N, Tanonaka K, Hara J (2003) A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats. Br J. Pharmacol. 138:642-54        Ueda M, Fujita R, Koji T, Ueda H. (2004) The cognition-enhancer nefiracetam inhibits both necrosis and apoptosis in retinal ischemic models in vitro and in vivo. J Pharmacol Exp Ther. 309:200-7.        Zhao X, Yeh J Z, Narahashi T. Post-stroke dementia. (2001) Nootropic drug modulation of neuronal nicotinic acetylcholine receptors. Ann N Y Acad. Sci. 939:179-86        US2001/0041734 A1 Method of treating traumatic brain injury and other neuronal disorders        US2002/0055534 A1 Method for treating neurodegeneration        U.S. Pat. No. 6,348,489 Method of treating traumatic brain injury and other neuronal disorders        U.S. Pat. No. 6,420,416 Method of treating epilepsy        U.S. Pat. No. 6,423,739 Method for aiding cerebral recovery following neurodegeneration        US2001/0051653 A1 Method for improving disturbances of activities of daily living after stroke        U.S. Pat. No. 6,399,650 Method for improving disturbances of activities of daily living after stroke        WO2003/030900 REMEDIES FOR ATTENTION-DEFICIENT/HYPERREACTIVITY DISORDER        WO2001/076596 MEDICINE FOR TREATING TRAUMATIC BRAIN INJURY AND OTHER NEURONAL DISORDERS        US2004/0192759 A1 Use of nefiracetam for treating neurodegeneration        US2008/0076820 A1 METHOD FOR TREATING NEURODEGENERATION        US2006/0241144 A1 Method for treating apathy syndrome        EP1171123 B1 METHOD FOR TREATING NEURODEGENERATION        WO2001/062246 A1 METHOD FOR TREATING NEURODEGENERATION        WO2006/113937 A2 METHOD FOR TREATING APATHY SYNDROME        WO2006/113937 A3R4METHOD FOR TREATING APATHY SYNDROME        EP1420782 B1 USE OF NEFIRACETAM FOR TREATING POST-STROKE NEURODEGENERATION        WO2003/018005 A1 Use of nefiracetam for treating neurodegeneration        
In one embodiment, the Active is formulated for oral administration and contains between 1 and 50 mg of active. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate, polyethylene glycol, polysorbate 80, and titanium dioxide. Alternatively, the inactive ingredients may include colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, and titanium dioxide.
In this specification, the term “combination therapy” should be taken to mean that the two therapies (immune mediated therapy and Active-mediated remyelination therapy) are carried out at the same time on the mammal. Thus, the two pharmaceutically-active agents (for example an immune mediated therapeutic such a TYSABRI and an Active such as NEFIRACETAM) may co-administered to an individual, in the form of a single formulation, be it a solid or liquid form, or may be provided as physically separate drugs that are co-administered to the individual, or they may be administered at staggered intervals.
In this specification, the term “pharmaceutical composition” should be taken to mean compositions comprising a therapeutically effective amount of an Active, and immunosuppressant (as defined above) and a pharmaceutically acceptable carrier or diluent. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the 2-oxypyrollidone compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, water, dried skim milk, glycerol, and propylene glycol.
The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, and sustained-release formulations
The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to, ease pain at the, site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
In a preferred embodiment of the invention, the mammal is a human, typically a human suffering from a disease or condition characterised by demyelination of CNS or PNS neuronal cells (i.e. a demyelination disease) such as MS.